1. Field of the Invention
The present invention relates to chimeric glycoproteins and improved lentiviral vectors pseudotyped with those glycoproteins, methods and compositions for making such glycoproteins and vectors, and methods of in vitro and in vivo transduction of cells with such vectors. The improved compositions and vectors are of particular utility for in vivo gene transfer applications.
2. Description of Related Art
Vectors derived from retroviruses offer particularly flexible properties in gene transfer applications given the numerous possible associations of various viral surface glycoproteins (determining cell tropism) with different types of viral cores (determining genome replication and integration)1. For example, association of the VSV-G glycoprotein with viral cores derived from lentiviruses results in vector pseudotypes that have broad tropism and can integrate into non-proliferating target cells2. They have proved useful for the transduction of several cell types ex vivo and in vivo3-7. Yet there is considerable interest in exploring the properties of lentiviral vectors pseudotyped with alternative viral glycoproteins8-15. This parameter is likely to modulate the physico-chemical properties of the vectors, their interaction with the host immune system and their host-range. Several studies have indeed shown that the transduction efficiency of target cells is dependent on the type of glycoprotein used to coat retroviral vectors16-21. Additionally, some in vivo gene transfer applications will require vectors that are targeted for specific cell entry and/or gene expression after systemic administration22. Due to the wide distribution of its receptor, a lipid component of the plasma membrane23, VSV-G pseudotypes may bind to the surface of all cells encountered after inoculation before reaching the target cells. Moreover, VSV-G-pseudotyped vectors are rapidly inactivated by human serum24 and this might impose a limitation on the use of VSV-G as a glycoprotein to pseudotype vectors for systemic gene delivery.
Lentiviral vectors derived from simian immunodeficiency virus (SIV) have been generated in several laboratories1, including our own25. Characterization of these vectors has indicated that they are similar to those derived from human immunodeficiency virus (HIV-1) with respect to the insertion of transgenes in non-proliferating cells, although SIV vectors perform better than HIV-1 vectors in simian cells25.